ABSTRACT (30 Lines Max) Objective: Develop two innovative high-speed 3D breast photoacoustic computed tomography (PACT) systems to diagnose benign, atypical, and malignant lesions ? leading to a more streamlined and accurate workup that reduces unnecessary follow-up imaging and benign breast biopsies. Clinical significance: Abnormal findings detected by screening mammography lead to workups including additional imaging, usually in the form of extra mammogram views, tomosynthesis, and/or ultrasound, and possibility of breast biopsy. Biopsies have considerable side effects such as pain and bleeding, and are unnecessary in the majority (60 ? 70%) of cases because of the high false-positive rate of mammography. The side effects, costs, and delays of the workups cause considerable stress to patients. PACT combines the functional optical contrast of diffuse optical tomography and the high spatial resolution of ultrasonography without speckle artifacts. The attenuation coefficient of near-IR light in breast tissue is only twice that of mammographic x-ray?enabling adequate optical penetration, but light has far higher soft-tissue contrast than x-ray. With rich functional contrast at high spatial and temporal resolutions and without using ionizing radiation or exogenous contrast agents, 3D breast PACT has the potential to reduce unnecessary benign breast biopsies by serving as a diagnostic tool adjunct to mammography. Possible long-term breast imaging applications include not only diagnosis, but also screening, assessment of response to pre-operative systemic therapy, and definitive surgical planning. Challenges: Numerous innovations are required to develop a PACT imaging system effective for clinical breast imaging. Previous PACT breast imagers possess significant limitations, including suboptimal light delivery, limited detection view, non-isotropic spatial resolution, and long scanning times. There remains an imperative need for more advanced PACT breast imaging technologies. Solutions: Encouraged by the preliminary deep and clear in vivo breast images acquired by our newly developed PACT system, we propose further innovations for 3D functional breast imaging to overcome the above-mentioned limitations. Aim 1: To develop a single-breath-hold 3D breast imaging system with nearly isotropic 3D resolutions and dual-wavelength contrasts (Model I). Aim 2: To develop a snapshot 3D breast PACT system (Model II) using the concept of acoustic ergodicity. It can reach the ultimate imaging speed (single laser shot), desirable for 3D high-resolution functional and dynamic imaging without motion artifacts. Both systems can perform elastography. Contrasts to be imaged include vascularity, concentration and oxygen saturation of hemoglobin, elasticity, and tumor volume and shape. Aim 3: To test PACT for the diagnosis of benign, atypical, and malignant breast lesions by comparing with the gold standard of tissue pathology.